Rethinking Matrigel: The Complex Journey to Matrix Alternatives in Organoid Culture

Matrigel is a crucial tool in cell biology, particularly for organoid research. It forms a stable scaffold with components like basement membrane proteins and growth factors, resembling the extracellular matrix and mimicking the cellular microenvironment. Its complex composition is both an asset and a drawback, as it is undefined and can vary from batch to batch. Another issue is the murine origin of Matrigel, raising ethical and scientific concerns. Interspecies variation hinders the successful translation of research findings from experimental models to clinical application in humans. Despite these well-known and often-discussed disadvantages, Matrigel is often the first choice of matrix. This review explores why Matrigel remains the gold standard for many human 3D culture systems despite its murine origin and well-known limitations. Therefore, challenges are identified that prevent researchers from transitioning to matrix alternatives and, eventually, developing completely xeno-free human model systems. To tackle these challenges, it is suggested to move beyond a one-for-all approach by pursuing a tissue- and model-specific focus when designing new matrices or selecting an alternative from already available options. To facilitate the implementation of Matrigel substitutes, we provide a matrix selection checklist and a scaffold assessment tool, and quantitative assessment criteria to evaluate matrix-model compatibility are suggested.